Calcineurin (Protein phosphatase 3) (CaN)

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that serves as a critical signaling hub in T-lymphocyte activation [UniProt: P16298]. Upon T-cell receptor stimulation, rising intracellular calcium levels activate calcineurin, which then dephosphorylates the Nuclear Factor of Activated T-cells (NFAT) [PubMed: PMC3135650]. This dephosphorylation enables NFAT to translocate from the cytoplasm to the nucleus, where it promotes the expression of interleukin-2 (IL-2) and other cytokines necessary for the immune response [StatPearls: Calcineurin Inhibitors]. Due to this central role, calcineurin is the primary target for potent immunosuppressive agents like cyclosporine and tacrolimus, which are used to prevent graft rejection and manage autoimmune conditions [NCBI: NBK532918]. Despite their efficacy, these drugs carry significant risks of nephrotoxicity and metabolic disturbances because calcineurin also regulates physiological processes in non-immune tissues like the kidneys and brain [PubMed: PMC4401143].

Other names

Protein phosphatase 2BPP2BPPP3CAPPP3CBPPP3CCPPP3R1PPP3R2Calcium-dependent serine-threonine phosphatase

Calcineurin inhibitors (CNIs) bind to intracellular immunophilins (cyclophilin for cyclosporine, FKBP12 for tacrolimus) to form a complex that sterically inhibits the phosphatase activity of calcineurin. This prevents the dephosphorylation of the Nuclear Factor of Activated T-cells (NFAT), thereby blocking its translocation to the nucleus and the subsequent transcription of pro-inflammatory cytokines such as Interleukin-2 (IL-2) [StatPearls: Calcineurin Inhibitors].